Penicillins and cephalosporins are β-lactam antibiotics that are widely and frequently used in the clinic. However, the acquisition of resistance to β-lactam antibiotics by various pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections. The most significant known mechanism related to the acquisition of bacterial resistance is the production of class A, C, and Dβ-lactamases having a serine residue at the active center. These enzymes decompose the β-lactam antibiotic, resulting in the loss of the antimicrobial activities. Class Aβ-lactamases preferentially hydrolyze penicillins while class Cβ-lactamases have a substrate profile favoring cephalosporins.
Commercially available β-lactamase inhibitors, e.g., clavulanic acid, sulbactam, and tazobactam, are known and these inhibitors are effective mainly against class Aβ-lactamase producing bacteria, and used as a mixture with a penicillin antibiotic. However, 250 types or more of β-lactamases have been reported to date, including resistant bacteria which produce class A KPC-2 β-lactamase decomposing even carbapenem.
In recent years, infectious diseases caused by the above-mentioned resistant bacteria as pathogenic bacteria are found not only in severe infectious disease but also occasionally in community-acquired infectious disease. The currently available β-lactamase inhibitors are insufficient to inhibit the incessantly increasing β-lactamase and novel β-lactamase inhibitors which are required for the difficult treatment of bacterial infectious diseases caused by resistant bacteria. The development of antibacterial agents as well as β-lactamase inhibitors is in strong demand as the commercially available inhibitors become increasingly ineffective.
One of these antibacterial agents, (2S, 5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, represented by Compound (I), is a “potent, broad-spectrum, non-β-lactam β-lactamase inhibitor” useful for antibiotic-resistant Gram-negative bacteria (Li, H.; Estabrook, M.; Jacoby, G. A.; Nichols, W. W.; Testa, R. T.; Bush, K. Antimicrob Agents Chemother 2015, 59, 1789-1793.) There are four crystalline forms of (2S, 5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide previously characterized and known in the art (see, e.g., International Publication no. WO 2015/053297).
While other crystalline forms have been previously characterized, large scale-up manufacturing processes which afford good reproducibility, high stability and high yield had not been achieved. When developing technologies for the commercial process, there are several factors and properties to consider when converting a small-scale lab process to a large manufacturing process suitable for clinical use.
One such factor includes solid state physical properties, for example, which entails the flowability of the milled solid, rate of dissolution and stability. The physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular crystalline form of a substance. A crystalline form may give rise to thermal behavior different from that of the amorphous material or another crystalline form. Thermal behavior is measured in the laboratory using techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). These techniques may be used to distinguish between different crystalline forms. A particular crystalline form may show distinct spectroscopic properties that can be detected using powder X-ray diffractometry (XRPD), nuclear magnetic resonance (NMR) spectrometry, Raman spectroscopy and infrared (IR) spectrometry.
In deciding which crystalline form is preferable, the numerous properties of the crystalline forms must be compared and the preferred crystalline form chosen based on the many physical property variables in order to determine which properties afford a suitable manufacturing process which allows clinical use. In other processes, a particular crystalline form may be preferable in certain circumstances in which specific aspects, such as ease of preparation, stability, etc., are deemed to be critical. In other situations, a different crystalline form may be preferred for greater solubility and/or superior pharmacokinetics.